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Genomic approaches in yeast have pioneered a whole new era in biology and they have enable technologies with a direct application to the field of natural/synthetic chemical products. We are applying yeast chemical-genetics approaches to gain insights into the mechanism of drug action. Perhaps the most powerful approach is the chemical-genetic information obtained from scoring each of the ~5000 viable deletion mutant strains for sensitivity to a specific compound using a parallel growth assay and barcode microarray readout.

Each mutant carries a unique 20 base pair oligonucleotide barcode, which upon amplification and hybridization to a barcode microarray provides information on the abundance of the mutant in a particular growth assay [Giaever et al., Nature 418:387-391 (2002)]. Thus, with a small volume of liquid growth medium, all ~5000 deletion mutants can be scored for fitness in the presence of a bioactive active compound.

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Figure 6

Gene deletions that render cells hypersensitive to a specific compound identify pathways that buffer the cell against the toxic effects of the compound. We created a detailed compendium of chemical-genetic interaction profiles, the set of viable gene deletion mutants that are hypersensitive to a particular compound, and found that clustering of the results organizes yeast genes into functional pathways but also organizes compounds into related sets with similar biological functions [Parsons et al., Cell 126:611-625 (2006)] (Fig.6). Thus, chemical-genetic profiling with yeast has proven to be a powerful new system for determining the mode-of-action of bioactive molecules.

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Figure 7

Because a deletion mutant provides a good model for the physiological effects of an inhibitory compound, the yeast synthetic lethal genetic interaction map provides a key for interpretation of the chemical-genetic profile of a compound [Parsons et al., Nature Biotechnology 22, 62 - 69 (2004)] (Fig.7).

In a proof-of-principle study, we've shown that compounds whose chemical-sensitivity profile resemble the synthetic lethal genetic interaction profile of a specific query gene may very well target the product of the identified gene or its corresponding pathway. We are comparing our synthetic lethal and chemical-genetic interaction networks computationally and predicting the targets pathways of specific compounds.